Rett syndrome (RS) is a neurodevelopmental disorder which affects females only and results in severe mental retardation and specific motor and behavioral abnormalities. The majority of RS cases are sporadic, however, familial cases have been documented suggesting that Rett syndrome is a genetic disorder. The familial cases and the exclusive occurrence of the syndrome in females suggest X-linked dominant inheritance with lethality in males, but X-linked or autosomal dominant inheritance with sex-limited expression is also considered. The overall goal of this research proposal is to map and identify the genetic defect in RS. Towards this goal, experiments are designed to investigate the various genetic models for RS. Assuming the X-linkage hypothesis, selected genes within regions concordant in familial RS cases will be evaluated for mutations that lead to loss of function or to inappropriate expression from the inactive X in Rett females. To pursue the identification of the RS mutation irrespective of the model of inheritance or map position, the genomes of RS patients will be compared with those of their parents using representational difference analysis (RDA). Under the hypothesis that sporadic RS cases result from new mutations, RDA is expected to identify de novo mutations/rearrangements. To investigate the hypothesis that RS is an autosomal disorder caused by mutations(s) which have sex-limited penetrance, genetic mapping studies will be carried out in a family with recurrent RS. A genome-wide scan for regions identical-by-descent will identify autosomal candidate regions which may harbor the RS gene. Lastly, to investigate the hypothesis that RS is caused by mutations in a neuronal gene which is sexually-dimorphic, vertebrate homolog(s) of a Drosophila gene expressed exclusively in the brain of female fruitflies (yin) will be identified and characterized. If the vertebrate homolog of yin proves to be sexually-dimorphic in humans, it will be characterized in RS patients by sequence analysis. In summary, a variety of approaches will be pursued to map and identify the RS gene. Identification of the RS gene is crucial for early diagnosis and possibly therapeutic intervention, and for understanding the biology of this developmental disorder.